Roberto Lucchini

The role of metals in neurodegenerative processes: aluminum, manganese, and zinc.

Until the last decade, little attention was given by the neuroscience community to the neurometabolism of metals. However, the neurobiology of heavy metals is now receiving growing interest, since it has been linked to major neurodegenerative diseases. In the present review some metals that could possibly be involved in neurodegeneration are discussed. Two of them, manganese and zinc, are essential metals while aluminum is non-essential. Aluminum has long been known as a neurotoxic agent. It is an etiopathogenic factor in diseases related to long-term dialysis treatment, and it has been controversially invoked as an aggravating factor or cofactor in Alzheimers disease as well as in other neurodegenerative diseases. Manganese exposure can play an important role in causing Parkinsonian disturbances, possibly enhancing physiological aging of the brain in conjunction with genetic predisposition. An increased environmental burden of manganese may have deleterious effects on more sensitive subgroups of the population, with sub-threshold neurodegeneration in the basal ganglia, generating a pre-Parkinsonian condition. In the case of zinc, there has as yet been no evidence that it is involved in the etiology of neurodegenerative diseases in humans. Zinc is redox-inactive and, as a result of efficient homeostatic control, does not accumulate in excess. However, adverse symptoms in humans are observed on inhalation of zinc fumes, or accidental ingestion of unusually large amounts of zinc. Also, high concentrations of zinc have been found to kill bacteria, viruses, and cultured cells. Some of the possible mechanisms for cell death are reviewed.

From Manganism to Manganese-Induced Parkinsonism: A Conceptual Model Based on the Evolution of Exposure

Manganism is a distinct medical condition from Parkinson’s disease. Manganese exposure scenarios in the last century generally have changed from the acute, high-level exposure conditions responsible for the occurrence of manganism to chronic exposure to much lower levels. Such chronic exposures may progressively extend the site of manganese deposition and toxicity from the globus pallidus to the entire area of the basal ganglia, including the substantia nigra pars compacta involved in Parkinson’s disease. The mechanisms of manganese neurotoxicity from chronic exposure to very low levels are not well understood, but promising information is based on the concept of susceptibility that may place individuals exposed to manganese at a higher risk for developing Parkinsonian disturbances. These conditions include mutations of genes which play important pathogenetic roles in both Parkinsonism and in the regulation of manganese transport and metabolism. Liver function is also important in manganese-related neurotoxicity and sub-clinical impairment may increase the risk of Parkinsonism. The purpose and scope of this report are to explore the literature concerning manganese exposure and potential subclinical effects and biological pathways, impairment, and development of diseases such as Parkinsonism and manganism. Inhalation and ingestion of manganese will be the focus of this report.

Sub-Clinical Neurobehavioral Abnormalities Associated with Low Level of Mercury Exposure through Fish Consumption

In order to assess early neurotoxic effects associated with relatively low levels of mercury absorbed through fish eating, two groups of 22 adult male subjects, habitual consumers of tuna fish, and 22 controls were examined using a cross-sectional field study. The assessment included neurobehavioral tests of vigilance and psychomotor function, hand tremor measurements and serum prolactin assessment. Mercury in urine (U-Hg) and serum prolactin (sPRL) were measured in all exposed subjects and controls, whereas measurements of the organic component of mercury in blood (O-Hg) were available for only 10 exposed and six controls. U-Hg was significant higher among exposed subjects (median 6.5 microg/g of creatinine, range 1.8-21.5) than controls (median 1.5 microg/g of creatinine, range 0.5-5.3). The median values of O-Hg were 41.5 microg/l among the tuna fish eaters and 2.6 microg/l in the control group. Both U-Hg and O-Hg were significantly correlated with the quantity of fish consumed per week. Significant differences in sPRL were found between exposed (12.6 ng/ml) and controls (9.1 ng/ml). Individual sPRL were significantly correlated with both U-Hg and O-Hg levels. The neurobehavioral performance of subjects who consumed tuna fish regularly was significantly worse on color word reaction time, digit symbol reaction time and finger tapping speed (FT). After considering the education level and other covariates, the multiple stepwise regression analysis indicated that O-Hg concentration was most significantly associated with individual performance on these tests, accounting for about 65% of the variance in test scores.

NEUROLOGICAL IMPACTS FROM INHALATION OF POLLUTANTS AND THE NOSE-BRAIN CONNECTION

The effects of inhaled particles have focused heavily on the respiratory and cardiovascular systems. Most studies have focused on inhaled metals, whereas less information is available for other particle types regarding the effects on the brain and other extra-pulmonary organs. We review here the key available literature on nanoparticle uptake and transport through the olfactory pathway, the experimental data from animal and in vitro studies, and human epidemiological observations. Nanoparticles (<0.1 μm in one dimension) may easily reach the brain from the respiratory tract via sensory neurons and transport from the distal alveoli into the blood or lymph as free particles or inside phagocytic cells. These mechanisms and subsequent biologic responses may be influenced by the chemical composition of inhaled particles. Animal studies with ambient particulate matter and certain other particles show alterations in neuro-inflammatory markers of oxidative stress and central neurodegeneration. Human observations indicate motor, cognitive, and behavioral changes especially after particulate metal exposure in children. Exposure to co-pollutants and/or underlying disease states could also impact both the biokinetics and effects of airborne particles in the brain. Data are needed from the areas of inhalation, neurology, and metal toxicology in experimental and human studies after inhalation exposure. An increased understanding of the neurotoxicity associated with air pollution exposure is critical to protect susceptible individuals in the workplace and the general population.

Are Current Biomarkers Suitable for the Assessment of Manganese Exposure in Individual Workers

BACKGROUND Whole blood and urinary manganese have been measured in occupational and environmental studies for the assessment of exposure. The aim of this study was to assess the relationship between the airborne concentrations of manganese and these biological indicators. METHODS Environmental and biological monitoring was performed in a group of 94 employees in a ferroalloy production, who were exposed to manganese (Mn) oxides (MnO(2) and Mn(3)O(4)). The results were compared with those from a control group of 87 subjects not exposed to Mn. RESULTS Mn exposure levels ranged between 5 and 740 micrograms/m(3), with arithmetic and geometric mean and median values being 202.6, 97.6, and 150 micrograms/m(3), respectively. Arithmetic and geometric means for Mn in total blood (MnB) were, respectively, 10.3+/-3.8 and 9.7 micrograms/L in the exposed and 5.9+/-1.7 and 5.7 micrograms/L in the controls. For urinary Mn (MnU), arithmetic and geometric means were, respectively, 4.9+/-3.6 and 3. 8 micrograms/L in the exposed and 1.2+/-1.4 and 0.7 micrograms/L in the controls. On a group comparison, a significant relationship was found between high and low exposed subgroups, identified according to Mn atmospheric concentrations (MnA), for both MnB (F value=38.0, P > 0.0001) and MnU (F value=36.1, P > 0.0001). On a linear relationship, a correlation was observed between MnA and MnB (r=0. 34; r(2)=0.112; P=0.001), whereas no association was found between MnA and MnU. A significant relationship emerged also between MnB and MnU (r=0.48, r(2)=0.23, P < 0.0001). No association was observed between an index of cumulative exposure and the biological indicators of exposure. CONCLUSIONS These results confirm that MnB and MnU can discriminate groups of occupationally exposed workers from groups of nonexposed subjects. MnB is also related to the intensity of external exposure on a linear relationship, but given a high variability, it is not suitable for individual biological monitoring. Therefore, further research should focus on more accurate biomarkers of Mn exposure.

Adequacy and Consistency of Animal Studies to Evaluate the Neurotoxicity of Chronic Low-Level Manganese Exposure in Humans

The adequacy of existing animal studies to understand the effects of chronic low-level manganese exposures in humans is unclear. Here, a collection of subchronic to chronic rodent and nonhuman primate studies was evaluated to determine whether there is a consistent dose-response relationship among studies, whether there is a progression of effects with increasing dose, and whether these studies are adequate for evaluating the neurotoxicity of chronic low-level manganese exposures in humans. Neurochemical and behavioral effects were compared along the axis of estimated internal cumulative manganese dose, independent of the route of exposure. In rodents, motor effects emerged at cumulative doses below those where occupationally exposed humans start to show motor deficits. The main neurochemical effects in rodents were an increase in striatal gamma-aminobutyric acid (GABA) concentration throughout the internal cumulative dose range of 18 to 5300 mg Mn/kg but a variable effect on striatal dopamine concentration emerging at internal cumulative doses above ∼200 mg Mn/kg. Monkey studies showed motor deficits and effects on the globus pallidus at relatively low doses and consistent harmful effects on both the globus pallidus and the caudate and putamen at higher doses (> 260 mg Mn/kg). Internal cumulative manganese doses of animal studies extend more than two orders of magnitude (< 1 to 5300 mg Mn/kg) above the doses at which occupationally exposed humans show neurological dysfunction (10–15 mg Mn/kg). Since the animal data indicate that manganese neurotoxicity may be different at low compared to elevated exposures, most existing animal model studies might be of limited relevance for the risk assessment of chronic low-level manganese exposure to humans.

Advancing the science of developmental neurotoxicity (DNT): Testing for better safety evaluation

test Guidelines OPPtS 8706300 on DNt (US ePA, 1998) and in 2007 the Organization for economic Cooperation and Development (OeCD) endorsed a new OeCD DNt test Guideline 426 (OeCD, 2007). these guidelines are largely based on animal studies and are used as higher tiered, triggered tests based on structure activity relationships or evidence of neurotoxicity in standard adult, developmental, or reproduction studies (Makris et al., 2009). experts at the conference stated that these in vivo tests are unsuitable for screening large numbers of chemicals for many reasons including low throughput, high cost, and questions regarding reliability. there was also consensus that new, reliable, and efficient screening and assessment tools are needed for better identification, prioritization, and evaluation of chemicals with the potential to induce developmental neurotoxicity. the information obtained from these screening studies will likely also help to refine animal tests and to inform epidemiological studies.

Manganese exposure: cognitive, motor and behavioral effects on children: a review of recent findings.

Purpose of review Manganese (Mn) is an essential element, but can be neurotoxic when exceeding the homeostatic range. We reviewed the most recent human studies (from January 2011 to July 2012) regarding the association between Mn exposure and cognitive, motor and behavioral effects on children. Recent findings A total of 10 articles were located; data were collected from five different countries. Six studies showed adverse effect of Mn on cognitive function. The most adopted cognitive test was the Wechsler Intelligence Scale for Children (WISC) or some subtests from it and results suggest an inverse association of higher Mn exposure with lower intellligence quotient. Three studies focused on motor effects of Mn; two of them found a direct association of higher Mn exposure with increased motor impairment. Two studies assessed Mn impact on behavior; one of them showed a correlation between higher Mn in water and both internalizing and externalizing behavioral scores. Potential limitations of these studies included the lack of validated biomarkers and the lack of consideration of mixed co-exposure with other neurotoxic agents. Summary Despite some potential limitations of the reviewed studies, the adverse effects of manganese exposure on the developing brain is well demonstrated and preventive strategies should be promoted.

Hair as a biomarker of environmental manganese exposure.

The absence of well-validated biomarkers of manganese (Mn) exposure in children remains a major obstacle for studies of Mn toxicity. We developed a hair cleaning methodology to establish the utility of hair as an exposure biomarker for Mn and other metals (Pb, Cr, Cu), using ICPMS, scanning electron microscopy, and laser ablation ICPMS to evaluate cleaning efficacy. Exogenous metal contamination on hair that was untreated or intentionally contaminated with dust or Mn-contaminated water was effectively removed using a cleaning method of 0.5%Triton X-100 sonication plus 1 N nitric acid sonication. This cleaning method was then used on hair samples from children (n = 121) in an ongoing study of environmental Mn exposure and related health effects. Mean hair Mn levels were 0.121 μg/g (median = 0.073 μg/g, range = 0.011-0.736 μg/g), which are ∼4 to 70-fold lower than levels reported in other pediatric Mn studies. Hair Mn levels were also significantly higher in children living in the vicinity of active, but not historic, ferroalloy plant emissions compared to controls (P < 0.001). These data show that hair can be effectively cleaned of exogenous metal contamination, and they substantiate the use of hair Mn levels as a biomarker of environmental Mn exposure in children.

Cancer Incidence in World Trade Center Rescue and Recovery Workers, 2001–2008

Background: World Trade Center (WTC) rescue and recovery workers were exposed to a complex mix of pollutants and carcinogens. Objective: The purpose of this investigation was to evaluate cancer incidence in responders during the first 7 years after 11 September 2001. Methods: Cancers among 20,984 consented participants in the WTC Health Program were identified through linkage to state tumor registries in New York, New Jersey, Connecticut, and Pennsylvania. Standardized incidence ratios (SIRs) were calculated to compare cancers diagnosed in responders to predicted numbers for the general population. Multivariate regression models were used to estimate associations with degree of exposure. Results: A total of 575 cancers were diagnosed in 552 individuals. Increases above registry-based expectations were noted for all cancer sites combined (SIR = 1.15; 95% CI: 1.06, 1.25), thyroid cancer (SIR = 2.39; 95% CI: 1.70, 3.27), prostate cancer (SIR = 1.21; 95% CI: 1.01, 1.44), combined hematopoietic and lymphoid cancers (SIR = 1.36; 95% CI: 1.07, 1.71), and soft tissue cancers (SIR = 2.26; 95% CI: 1.13, 4.05). When restricted to 302 cancers diagnosed ≥ 6 months after enrollment, the SIR for all cancers decreased to 1.06 (95% CI: 0.94, 1.18), but thyroid and prostate cancer diagnoses remained greater than expected. All cancers combined were increased in very highly exposed responders and among those exposed to significant amounts of dust, compared with responders who reported lower levels of exposure. Conclusion: Estimates should be interpreted with caution given the short follow-up and long latency period for most cancers, the intensive medical surveillance of this cohort, and the small numbers of cancers at specific sites. However, our findings highlight the need for continued follow-up and surveillance of WTC responders.